The human retroviruses HIV~1 and HTLV~1 can both infect the central nervous system (CNS) causing the AIDS psychomotor complex and tropical spastic paraparesis, respectively. To study neurotropism of these viruses, we use primary cultures derived from adult human brain. As microglial cells are the major target cell of HIV~1 within the CNS, we have examined microglial cell tropism and molecular determinants within the V3 loop of gp 120 in 13 HIV~1 variants isolated from blood and~or cerebrospinal fluid (CSF) at early or advanced stages of AIDS. The majority of HIV~1 variants isolated from blood and CSF even in the asymptomatic stage of the disease, can infect microglial cells, although their V3 loop may differ substantially from each other. Thus , HIV~1 variants in blood or CSF of seropositive patients may infect microglia early in infection, establishing a virus reservoir in the CNS. In contrast, highly cytopathic syncytium~inducing viruses, isolated at an advanced stage of the disease, are less likely to replicate in primary human brain microglia. We have also investigated the role of tumor necrosis factor (TNF) alpha in HIV~1 encephalopathy using purified microglial cultures derived from adult human brain. Such cells are activated and express TNF alpha, just as they do in the brain tissue of patients with AIDS psychomotor complex. When infected with HIV~1 in the continuous presence of TNF alpha antibody, HIV~1 expression and virus growth in microglial cells are strongly inhibited for over a week, suggesting that TNF alpha naturally produced in this in vitro system may enhance HIV~1 replication. Moreover, microglial cell~derived TNF alpha may be toxic for oligodendrocytes, the CNS myelin~forming cells and cause the demyelination observed in the HIV~1 leucoencephalopathy. To investigate this possibility, we have developed an in vitro assay in which TNF alpha induced~cell death of purified rat and~or human oligodendocytes can be accurately measured. Thus, TNF alpha may indirectly damae some CNS cells and enhance HIV~1 expression and spread within the CNS.